反应详情

温度

80 °C

A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide (Stage 92.1, 175 mg, 0.343 mmol), 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (201 mg, 0.687 mmol), K3PO4 (219 mg, 1.030 mmol) and Pd(PPh3)4 (19.9 mg, 0.017 mmol) and toluene (2 mL) were added to a vial, which was sealed purged with argon stirred at 80° C. for 24 h. EtOAc (60 mL) was added and the solution was washed with aq. sat. NaHCO3 solution (20 mL) and brine (2×20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 40 g, DCM/MeOH 95:5). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.554 mL, 7.19 mmol) and stirred at RT for 18 h. The RM was dissolved in EtOAc, washed with aq. sat. NaHCO3 solution and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing product were combined and the solvent was evaporated off under reduced pressure to give an MeCN aq. residue which was treated with Na2CO3 (1 g) and extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (1: Column DEAP, from 20% to 25% in 11 min; 2: Column PFP, from 5% to 10% in 11 min) to give the title product as a white solid. HPLC (Condition 7) tR=5.675 min, UPLC-MS (Condition 8) tR=0.95 min, m/z=464.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.28 (br. s, 3H) 2.57-2.68 (m, 1H) 3.42-3.49 (m, 2H) 3.50-3.57 (m, 2H) 3.72-3.88 (m, 2H) 4.71 (br. s, 1H) 6.16 (s, 1H) 7.33 (d, J=8.53 Hz, 2H) 7.87 (d, J=8.91, 2H) 8.01 (s, 1H) 8.70 (br. s, 1H) 10.21 (s, 1H).

1. additionwere added to a vial, which
2. customwas sealed
3. custompurged with argon
4. additionEtOAc (60 mL) was added
5. washthe solution was washed with aq. sat. NaHCO3 solution (20 mL) and brine (2×20 mL)
6. dry with materialdried over Na2SO4
7. customthe solvent was evaporated off under reduced pressure
8. customto give a residue which
9. customwas purified by flash chromatography (RediSep® Silica gel column, 40 g, DCM/MeOH 95:5)
10. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
11. stirringstirred at RT for 18 h
12. washwashed with aq. sat. NaHCO3 solution and brine
13. dry with materialdried over Na2SO4
14. customthe solvent was evaporated off under reduced pressure
15. customto give the crude product which
16. customwas purified by preparative HPLC (Condition 10)
17. additionFractions containing product
18. customthe solvent was evaporated off under reduced pressure
19. customto give an MeCN aq. residue which
20. extractionextracted with EtOAc
21. washThe combined organic phases were washed with water
22. dry with materialdried over Na2SO4
23. customthe solvent was evaporated off under reduced pressure
24. dissolutionThe residue was dissolved in MeOH (3 mL)
25. filtrationfiltered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge
26. washwas washed with MeOH
27. customthe solvent was evaporated off under reduced pressure
28. customto give a residue which
29. customwas purified by preparative SFC (1: Column DEAP, from 20% to 25% in 11 min; 2: Column PFP, from 5% to 10% in 11 min)